The project is to develop a vaccine strategy against HIV infection that is based on an "experiment of nature" in which resistance to HIV infection is found in subjects with homozygous A32 CCR5 mutation. The specific aims are to develop a simian model of the delta32 CCR5 mutation by (a) blocking and downmodulating the CCR5 coreceptors which are involved in primary mucosal HIV infection and (b) eliciting mucosal, regional lymph node and systemic immunity against the virus. The strategy is to use a microbial70kD heat shock protein (HSP70) which stimulates production of CC chemokines and functions as an adjuvant. Immunization with the extracellular peptides of CCR5 linked toHSP70 elicits antibodies to the CCR5, as well as CC chemokines. This will be combined with specific SIV targeted immunization, by using SIV envelope gp120 and gag p27. Immunization with the SIV-CCR5 vaccine will be carried out by the rectal route in rhesus macaques and compared with those administered SIV-HSP70 or CCR5-HSP70. Broadly based innate and adaptive immune responses will be monitored in themucosal and systemic compartments before and after each immunization. The animals will be challenged 4 weeks after the 3 rd immunization with SIVmac 251. They will be monitored for plasma viral load, CD4 v T cell count and IFN'y for 24 weeks, at which time the animals will be killed and the viral load determined in mucosal tissues, lymph nodes and spleen. This novel immunization strategy, designed to generate innate and adaptive immunity, and targeting both the virus and its primary coreceptors may prove an effective approach in preventing or controlling HIV infection.